The peroxisome proliferator-activated receptor gamma-retinoid X receptor (PPARy-RXR) transcriptional complex regulates energy balance by controlling genes involved in the metabolism, uptake, oxidative combustion and storage of fatty acids (FAs) and glucose. The PPARy-RXR complex also modulates inflammation, oxidant stress and atherosclerosis, including through their effects in the endothelium. Although endothelial function is usually defined in terms of vasomotor reactivity, we hypothesize the endothelium is also involved in the control of systemic metabolism. We found that endothelial PPARy-deficient mice fed a high fat diet manifest decreased adiposity and improved insulin sensitivity but markedly elevated FA and triglyceride (TG) levels and impaired endothelial reactivity, all as compared to control mice. As such, these mice (Tie2Cre/floxed PPARy mice with and without bone marrow transplantation) disassociate metabolic and vascular components of endothelial function, providing opportunities for studying endothelial control of metabolism. Aim 1 will investigate how endothelial PPARy's control of FA and glycerol levels influences endothelial responses, hepatic TG accumulation and insulin sensitivity. Aim 2 will investigate the source of the increased oxidant stress evident in endothelial PPARydeficient mice, including the role of oxidation in endogenous PPARy ligand formation. Although we and others have shown that PPARy can inhibit endothelial inflammatory responses, including endothelial chemokine expression, the mechanisms for this trans-repression have remained unclear. Aim 3 will investigate the evidence provided here that post-translatioiial SUMOylation of PPARy is involved in PPARymediated repression of specific chemokine subsets and leukocyte recruitment, including inflammatory cell recruitment to adipose tissue. Although all these and other PPARy actions require RXR as an obligate heterodimeric PPARy partner, very little is known about the role of retinoid metabolism and RXR activation in the endothelium. We recently reported that retinaldehyde, which is converted by retinaldehyde dehydrogenase (RaIdh) to retinoic acid (RA), is present in fat where it can repress PPARy-RXR activity. Raldhi-deficient mice, which have increased Raid in fat, are completely protected against diet-induced obesity and diabetes. Aim 4 will investigate pathways of retinoid metabolism in endothelial cells and the sources of the increased oxidant stress in Raldhi-deficient mice shown here. Together these studies, through close collaboration with the other Projects and Core Laboratories, will identify how the endothelial PPARy-RXR complex is involved in integrating metabolic and vascular components of endothelial function.

Public Health Relevance

Obesity and diabetes are characterized by high glucose and fatty acid levels, which may contribute to the heart disease so common in these patients. We have found that the inner lining of arteries - the endothelium - nlay help control systemic levels of fatty acids and glucose through two proteins - the peroxisome proliferator-activated receptor gamma (PPARy) and the retinoid X receptor (RXR) - that work together to control whether certain genes are turned off or on. These studies offer new ways to understand connections between the endothelium, diabetes and heart disease.